Safety and efficacy of continuous infusion terlipressin (BIV201): A phase 2 trial in patients with decompensated cirrhosis and refractory ascites

Metformin for patients with metastatic prostate cancer starting androgen deprivation therapy: a randomised phase 3 trial of the STAMPEDE platform protocol.

Low-dose ketamine has been used perioperatively for pain control and may be a useful adjunct to intravenous (IV) opioids in the control of acute pain in the emergency department (ED). The aim of this study was to determine the effectiveness of low-dose ketamine as an adjunct to morphine versus standard care with morphine alone for the treatment of acute moderate to severe pain among ED patients. A double-blind, randomized, placebo-controlled trial with three study groups was conducted at a large, urban academic ED over a 10-month period. Eligible patients were 18 to 65 years old with acute moderate to severe pain (score of at least 5 out of 10 on the numerical pain rating scale [NRS] and pain duration < 7 days) who were deemed by their treating physician to require IV opioids. The three study groups were: 1) morphine and normal saline placebo (standard care group), 2) morphine and 0.15 mg/kg ketamine (group 1), or 3) morphine and 0.3 mg/kg ketamine (group 2). Participants were assessed at 30, 60, and 120 minutes after study medication administration and received rescue analgesia as needed to target a 50% reduction in pain. The primary outcome measure of pain relief, or pain intensity reduction, was derived using the NRS and calculated as the summed pain-intensity (SPID) difference over 2 hours. The amount and timing of rescue opioid analgesia was evaluated as a secondary outcome. The occurrence of adverse events was also measured. Sixty patients were enrolled (n = 20 in each group). There were no differences between study groups with respect to age, sex, race/ethnicity, preenrollment analgesia, or baseline NRS. Over the 2-hour poststudy medication administration period, the SPIDs were higher (greater pain relief) for the ketamine study groups than the control group (standard care 4.0, interquartile range [IQR] = 1.8 to 6.5; group 1 7.0, IQR = 4.3 to 10.8; and group 2 7.8, IQR = 4.8 to 12.8; p < 0.02). The SPIDs for the ketamine groups were similar (p < 0.46). When compared to standard care, group 2 sustained the reduction in pain intensity up to 2 hours, whereas group 1 was similar to standard care by 2 hours. Similar numbers of patients received rescue analgesia: standard care group, seven of 20, 35%; group 1, four of 20, 20%; and group 2, four of 20, 20% (p = 0.48). Among those receiving rescue analgesia, those in the standard care group received analgesia sooner than either low-dose ketamine group, on average. More participants in the low-dose ketamine groups reported dysphoria and dizziness. Low-dose ketamine is a viable analgesic adjunct to morphine for the treatment of moderate to severe acute pain. Dosing of 0.3 mg/kg is possibly more effective than 0.15 mg/kg, but may be associated with minor adverse events. Future studies should evaluate additional outcomes, optimum dosing, and use in specific populations.

Background and Aims Hepatorenal syndrome (HRS) is one of the complications among patients with cirrhosis. Available guidelines recommended terlipressin with albumin as part of HRS management. To date there is no consensus on whether terlipressin should be given via bolus or continuous intravenous infusion. This study aims to compare the effectiveness and safety of continuous intravenous infusion versus intravenous boluses of terlipressin in the treatment of patients with HRS and cirrhosis. Method A comprehensive search for databases of randomized controlled trials (RCTs) comparing continuous intravenous infusion versus intravenous boluses of terlipressin among adult patients with hepatorenal syndrome was done. PubMed, EMBASE, the Cochrane Library, and ClinicalTrials.gov were searched using relevant terms including hepatorenal syndrome, acute kidney injury, cirrhosis, terlipressin, bolus, and continuous infusion until December 2023. Response to therapy defined as decrease in serum creatinine or regression of acute kidney injury was the primary outcome of interest, while safety in terms of drug-related events, mortality, and transplant-free survival were the secondary outcomes. Data extraction was performed using a standardized data form. The reviewers independently screened the studies and assessed the methodological quality using the Cochrane Risk of Bias tool and any discrepancies were resolved by consensus among the authors. Random-effects meta-analysis was done using Review Manager 5.4. Results A total of three studies, one high quality and two moderate quality RCTs, were included in the review, involving a total of 240 patients. Pooled analysis showed that continuous infusion was as effective or better than bolus infusion in achieving the primary outcome (RR 1.12, 95% CI 0.95-1.32, I2 = 0%). In one study, 28- and 90-day mortality were not significantly different, while 90-day transplant-free survival was not significantly different between continuous and bolus groups from another trial (53% vs 69% p = 0.26). Higher incidence of adverse events were also reported in the bolus group, RR 0.37, 95% CI 0.13-1.04 (p = 0.06). Conclusion There is limited evidence to suggest that continuous infusion of terlipressin may demonstrate resolution of acute kidney injury more frequently than bolus infusion, and that continuous infusion is associated with decreased adverse events. Larger randomized controlled trials with higher quality are needed to ascertain the effects on mortality, need for renal replacement therapy, and transplant-free survival.

We read with interest the study by Eriksen et al. regarding the impact of terlipressin on plasma sodium (PNa).1 An analogue of vasopressin, terlipressin is used to treat the effects of systemic vasodilatation and renal dysfunction in patients with portal hypertension. It acts on vascular smooth muscle V1 receptors to induce splanchnic vasoconstriction and on renal collecting duct V2 receptors to mobilise aquaporin channels.2 Eriksen et al. noted that these effects promote hyponatraemia and hypothesised that this may be more profound in non-cirrhotic patients, who do not demonstrate urinary sodium retention or high aquaporin expression at baseline.2 The authors retrospectively compared PNa fluctuations in non-cirrhotics and cirrhotics with portal hypertension receiving bolus terlipressin for variceal bleeding. They found that non-cirrhotic patients had a greater reduction in mean PNa during terlipressin therapy (8.3 vs. 1.8 mmol/l, p = 0.048) and a larger increase in mean PNa post its cessation (12.6 vs. 2.3 mmol/l, p = 0.03). In both groups, an increased cumulative dose and duration of terlipressin was associated with more marked hyponatraemia (p = 0.009 vs. p = 0.02). They concluded that terlipressin posed a potentially dangerous risk of hyponatraemia in non-cirrhotic patients with variceal bleeding. We agree that clinicians using terlipressin in this setting should proceed with caution, but offer safety data regarding its prolonged use in cirrhotic patients with other portal hypertensive complications. Based on safety and efficacy data from a Cochrane review and randomised control trial,3, 4 our centre has developed a protocol for delivering continuous terlipressin infusion (CTI) in the outpatient setting to cirrhotics with hepatorenal syndrome (HRS) (as defined by the International Club of Ascites)5 or refractory ascites who are awaiting liver transplantation. We have therefore prospectively observed the effect of CTI on PNa in this novel cohort. Data was collected on all patients who received at least two weeks of CTI prior to 31 March 2018. Patients commenced bolus terlipressin as inpatients (0.85 mg Q6h) and received volume expansion with albumin (40 g/day for three days). Suitable patients were transitioned to CTI. Informed consent was obtained and patients were transitioned to outpatient CTI, delivered via a peripherally inserted central catheter and SureFuser pump managed by our hospital-in-the-home program. We measured PNa at baseline, during terlipressin therapy (daily as inpatients, weekly as outpatients) and at final follow-up (liver transplantation, CTI cessation or 31 March 2018). This was approved by the Austin Health Human Research Ethics Committee. Additional data regarding nutritional outcomes from this cohort can be found in Chapman et al.6 Nineteen patients received CTI for a median of 51 days (IQR 29–222) (Table 1) and during this time mean PNa increased by 4.5 mmol/l (131.2–135.6 mmol/l, p = 0.008) (Figure 1). CTI was associated with a reduction in mean model for end stage liver disease with sodium (MELD-Na) score by 6 (27.1 to 21.1, p < 0.001). At final follow-up, 14 patients had undergone liver transplantation, three remained on CTI and two had ceased CTI (n = 1 recovery post hepatitis C eradication, n = 1 alcohol recidivism and delisting). There were no adverse events attributed directly to terlipressin therapy. Mean plasma sodium (mmol/L) over time. The difference in PNa profiles observed in the cirrhotic patients in Eriksen et al. and our cohorts is striking and warrants exploration. Potentially, mechanisms for this could relate to the disparate terlipressin dosing and indications. Bolus terlipressin results in higher daily doses and greater drug-level fluctuations compared with CTI,4 which might contribute to greater PNa variation. In addition, patients with variceal bleeding are often hypovolaemic and receive intravenous crystalloids or blood products only when indicated; whereas patients with HRS and refractory ascites routinely receive albumin for volume expansion. In a recent narrative review by Papaluca et al.,7 the one study in which terlipressin increased PNa in cirrhotic patients was the only to use albumin routinely,8 as also occurred in our study. The potential influence of albumin administration on natremia is multifaceted. As a negatively charged molecule, albumin exerts a ‘Gibbs–Donnan effect’ to draw cations such as sodium into the vascular compartment.9 Albumin is also a large protein, which increases oncotic pressure and therefore mobilises interstitial fluid into the intravascular space. This increases effective arterial blood volume, which subsequently downregulates baroreceptor activation, decreases endogenous vasopressin release and reduces water retention. Papaluca et al. postulated that this albumin-induced decrease in endogenous vasopressin might predominate over terlipressin-induced V2 receptor activation, with the net result being free water clearance.8 Ultimately, further research is needed to understand how terlipressin influences PNa, and the importance of factors beyond the patient's cirrhotic status.

Treatment Patterns and Real World Outcomes with Clinical Trials for Patients with Follicular Lymphoma across Lines of Therapy

To the Editor: Guidelines for HIV/hepatitis C virus (HCV)-coinfected patients recommend HCV treatment with pegylated interferon-α (PEG-IFN) plus ribavirin (RBV).1 The adverse effects of IFN/RBV, particularly anemia, may be more common among HIV/HCV-coinfected than HCV-monoinfected patients2 and are often associated with decreased health-related quality of life (HRQOL)3 as well as with discontinuation or dose reduction of RBV.4 This study evaluated the effectiveness of once-weekly (QW) epoetin alfa (epoetin alfa) compared with standard of care (SOC) in correcting anemia, improving HRQOL, and minimizing RBV dose reductions in HIV/HCV-coinfected patients receiving IFN/RBV therapy. This was a 16-week, open-label, randomized, parallel-group, multicenter study in anemic patients with HIV/HCV coinfection receiving IFN/RBV therapy for an anticipated period of ≥16 additional weeks. Key inclusion criteria included patient age of 18 to 75 years and hemoglobin (Hb) ≤12 g/dL or a ≥2-g/dL decrease in Hb after IFN/RBV initiation. Key exclusion criteria included a history of uncontrolled hypertension or seizure disorder, anemia attributable to another cause, and exposure to any epoetin within 3 months. Patients were randomized (1:1 ratio) to receive up to 16 weeks of epoetin alfa (PROCRIT™; Ortho Biotech Products, LP, Bridgewater, NJ) at a dose of 40,000 U subcutaneously QW or SOC (no epoetin alfa). Epoetin alfa dosage was increased to 60,000 U QW after 4 weeks of therapy if Hb had not returned to pre-IFN/RBV levels. Epoetin alfa was discontinued after an additional 4 weeks at 60,000 U QW if Hb had not increased ≥1.0 g/dL from the nadir Hb value. If Hb exceeded 14 g/dL in women or 16 g/dL in men, epoetin alfa was withheld temporarily. The primary end point was to compare the mean change in Hb from baseline (ie, first dose of study drug in epoetin alfa group, day 1 in SOC group) to week 16 in the epoetin alfa group with that in the SOC group. Secondary end points were mean change in RBV dosage, HRQOL scores (measured by modified Short Form-12 [SF-12] Health Survey-Acute; Physical and Mental Health Components [PCS, MCS]),5 and transfusion. Patients were required to complete HRQOL assessments before each visit. Safety assessments included monitoring vital signs, adverse events, alanine aminotransferase (ALT) levels, CD4+ counts, and HIV and HCV viral loads. Efficacy analyses were based on a modified intent-to-treat (MITT) population defined as all patients who had baseline Hb measured and had at least 1 follow-up Hb assessment and, for the epoetin alfa group, received at least 1 dose of epoetin alfa. Safety analysis considered all patients. Missing values were imputed for the efficacy analyses using the last-value-carried-forward technique. Changes in Hb and SF-12 PCS and MCS scores were analyzed within each treatment group using paired t tests and were compared between groups using an analysis of covariance (ANCOVA) model with treatment group as a factor and baseline values as a covariate. RBV dosage changes were assessed by on-treatment analysis and were analyzed using a Wilcoxon signed-rank test to compare between groups. A post hoc analysis of changes in Hb stratified by zidovudine (AZT) status was performed. The incidence of adverse events between groups was compared using the Fisher exact test. Sixty-six patients were randomized (34 to epoetin alfa group and 32 to SOC group). Baseline characteristics were comparable between the 2 groups. Immediately after randomization (day 1/week 0), 14 patients (4 epoetin alfa and 10 SOC) dropped out of the study without baseline or follow-up assessments. Compared with SOC patients included in the MITT analysis, early SOC dropout patients had lower Hb levels at study entry (10.3 vs. 11.5 g/dL; P = 0.03). Thirty epoetin alfa patients and 22 SOC patients were included in the MITT analysis. Twenty (63%) SOC patients and 11 (32%) epoetin alfa patients dropped out during the 16-week study period. The median time between initiation of IFN/RBV and baseline was 50 days (range: 16-306 days) in the epoetin alfa group and 60 days (range: 22-171 days) in the SOC group. Mean baseline Hb (±SE) was 11.1 ± 0.3 g/dL in the epoetin alfa group and 11.5 ± 0.3 g/dL in the SOC group (P = 0.33), and mean increases in Hb from baseline to week 16 were 2.6 ± 0.3 g/dL and 0.2 ± 0.3 g/dL, respectively (P < 0.001). No patient had epoetin alfa withheld because of reaching the upper limit of Hb. Patients receiving epoetin alfa and AZT had a greater mean increase in Hb from baseline to week 16 than those not receiving AZT (3.2 ± 0.4 g/dL [n = 13] vs. 2.1 ± 0.4 g/dL [n = 17]; Fig. 1). For SOC patients, the mean change in Hb was similar in AZT users and nonusers. No transfusions occurred.FIGURE 1: Hemoglobin (Hb) levels by treatment group stratified by zidovudine (AZT) treatment status (modified-intention-to-treat [MITT] population). *P = 0.001 versus standard of care (SOC) receiving AZT (analysis of covariance [ANCOVA]). †P < 0.001 versus SOC not receiving AZT (ANCOVA).Mean RBV doses at initiation of IFN/RBV and at baseline, respectively, were 1047 and 973 mg/d in the epoetin alfa group and 1027 and 982 mg/d in the SOC group. At week 16, 67% of epoetin alfa patients and 45% of SOC patients were receiving RBV doses ≥10.6 mg/kg/d (P = 0.09). The SF-12 PCS score (mean ± SE) increased significantly from baseline to week 16 in the epoetin alfa group (6.0 ± 1.8 points; P = 0.004), whereas the mean increase in the SOC group was not significant (2.2 ± 1.2 points; P = 0.09). The mean increase in the SF-12 MCS scale score was 2.3 ± 2.0 points in the epoetin alfa group and 0.1 ± 1.5 points in the SOC group (P = nonsignificant vs. baseline for both groups). There were no significant differences between groups for mean change from baseline to week 16 in the SF-12 PCS or SF-12 MCS scale score. Epoetin alfa was well tolerated, with most adverse events mild to moderate in severity. Patients treated with epoetin alfa had significantly less fatigue (n = 3 [10%]) compared with those in the SOC arm (n = 9 [38%]) (P = 0.02); there was no other significant difference between groups in the incidence of common adverse events. Four serious adverse events were reported: 1 in the epoetin alfa group (constipation, which was considered unrelated to epoetin alfa) and 3 in the SOC group (chest pain, myocardial infarction, and psychosis). There were no reports of thrombovascular events or antierythropoietin antibodies related to epoetin alfa. In this randomized study, epoetin alfa effectively corrected anemia in HIV/HCV-coinfected patients treated with IFN/RBV, including those taking AZT. The magnitude of Hb increase (mean = 2.6 g/dL) in coinfected patients was similar to that previously observed in IFN/RBV-related anemia in patients with HCV monoinfection.6,7 In contrast to studies in patients with HCV alone, no effect of epoetin on RBV dose was observed.6,7 A significant number of SOC patients dropped out after randomization (10 patients) and before week 16 (20 patients), however, substantially limiting our ability to assess the secondary end point of RBV dose, because patients and investigators may have selectively discontinued study participation in those SOC patients with worse outcomes. Improvements in HRQOL scores were greater in patients receiving epoetin alfa, but the small sample size precluded definitive conclusions. Significantly fewer patients treated with epoetin alfa than SOC reported fatigue as an adverse event. In conclusion, epoetin alfa was effective in correcting anemia and was well tolerated in HIV/HCV-coinfected patients receiving IFN/RBV therapy compared with SOC. Larger, double-blind, placebo-controlled studies as well as studies evaluating alternative criteria for the use of epoetin alfa are warranted to further assess the effects of epoetin alfa on HRQOL, maintenance of RBV dose, and HCV response. ACKNOWLEDGMENTS Coinvestigators include the following individuals: Philip Keiser, MD, University of Texas, Dallas, TX; David Bernstein, MD, North Shore University Hospital, Manhasset, NY; Christine Zurawski, MD, Office of Joel Rosenstock, MD, Atlanta, GA; Coleman Smith, MD, Minnesota Clinical Research Center, St. Paul, MN; Vilma Vega, MD, Infectious Diseases Associates, Sarasota, FL; Daniel Wolde-Rufael, MD, Chase Brexton Health Services, Baltimore, MD; Joseph Jemsek, MD, Jemsek Clinic, Huntersville, NC; Sangik Oh, MD, Beth Israel Deaconess Medical Center, Boston, MA; and Gerald Pierone, MD, Treasure Coast Infectious Disease Consultants, Vero Beach, FL. The authors acknowledge the contributions of Kimberly Marino, Bann-Mo Day, Nicole Slacik, Kevin Smith, and Angela Klopfer of Ortho Biotech Clinical Affairs, LLC. Mark S. Sulkowski, MD* Douglas T. Dieterich, MD† Edmund J. Bini, MD‡ Norbert Bräu, MD§ Daniel Alvarez, MD§ Edwin DeJesus, MD¶ Gerhard J. Leitz, MD# for the HIV/HCV Coinfection Study Group *Viral Hepatitis Center, Johns Hopkins University, Baltimore, MD †Mt. Sinai Medical Center, New York, NY, ‡Veterans' Administration, New York Harbor Healthcare System, New York, NY, §Bronx Veterans' Administration, Medical Center, Bronx, NY, §Drexel University College of Medicine, Philadelphia, PA, ¶IDC Research Initiative, Altamonte Springs, FL, #Ortho Biotech Clinical Affairs, LLC, Bridgewater, NJ

Continuous infusion of terlipressin causes more stable reduction in portal venous pressure than intermittent infusion. The aim of the study was to compare the efficacy of continuous infusion vs. intermittent boluses of terlipressin to control acute variceal bleeding (AVB) in patients with portal hypertension. Eighty-six consecutive patients with portal hypertension and AVB were randomized to receive either continuous intravenous infusion (Group A, n = 43) or intravenous boluses of terlipressin (Group B, n = 43). Group A received 1mg intravenous bolus of terlipressin followed by a continuous infusion of 4mg in 24h. Group B received 2mg intravenous bolus of terlipressin followed by 1mg intravenous injection every 6h. Upper gastrointestinal (UGI) endoscopy was done within 12h of admission. Endoscopic variceal ligation (EVL) was done using a multi-band ligator. In both groups, treatment was continued up to 5days. The primary endpoint was rebleeding or death within 5days of admission. Patients in group A had lower rate of treatment failure (4.7%) as compared to patients in group B (20.7%) (p = 0.02). Within 6weeks, four and eight patients died in group A and B, respectively (p = 0.21). Model for end-stage liver disease sodium (MELD-Na) score and continuous infusion of terlipressin showed significant relationship with treatment failure onmultivariate analysis. Continuous infusion of terlipressin may be more effective than intermittent infusion to prevent treatment failure in patients with variceal bleeding. There is significant relationship between MELD-Na score [Odd ratio = 1.37(95% CI-1.16 - 1.62), p-value < 0.001] and continuous infusion of terlipressin [Odd ratio = 0.18(95% CI-0.037 - 0.91), p-value - 0.04] with treatment failure.

Therapeutic options are limited for patients with hepatorenal syndrome (HRS), diuretic refractory ascites and hepatic hydrothorax who are awaiting liver transplant. We assessed the safety and efficacy of continuous terlipressin infusion (CTI) for treating these conditions in an outpatient setting. All patients treated with CTI from May 2013 through March 2018 at our institution were initiated in-hospital on bolus dose terlipressin therapy for 24-72 h prior to commencing CTI for home therapy. Daily home visits for clinical assessment and medication administration were provided. Adverse events, effects of treatment on renal function, model for end-stage liver disease (MELD) score, and paracentesis/thoracentesis requirements were assessed. Twenty-three patients were included (HRS = 17; refractory ascites = 4; refractory hepatic hydrothorax = 2). Median (range) duration of outpatient CTI was 50 (1-437) days with a total of 2482 patient days of treatment. Fourteen patients (60.9%) received a liver transplant; of whom 13 (92.9%) were alive at the end of the study period. There were no cardiac or ischemic complications and no serious adverse events reported. In patients with HRS, median serum creatinine significantly decreased from 202.0 μmol/L at baseline to 125.5 μmol/L at day 14 of CTI (P = 0.0003) and remained stable thereafter. Median MELD score decreased from 22.5 to 19.0 at end of CTI (P = 0.008). Median frequency of paracentesis/thoracentesis was 4 per month prior to CTI versus 1.52 during treatment. Transplant-eligible and otherwise stable patients can be managed with CTI at home for an extended duration under supervision without adverse consequences.

Early Interdisciplinary Palliative Care in Patients with Previously Untreated Metastatic Oesophagogastric Cancer: A Phase 3 Randomised Controlled Trial

The Effects of Romiplostim or Standard of Care (SOC) on Splenectomy and Treatment Failure of Patients Who Had Immune Thrombocytopenia (ITP) for Less Than or Equal to One Year.

In patients with sepsis, hemodynamic support is often complicated by a tachyphylaxis against conventional vasopressor agents. Bolus infusion of terlipressin, a vasopressin analog, has been reported to increase mean arterial pressure in patients with catecholamine-resistant septic shock. However, bolus infusion of terlipressin may be associated with severe side effects, including pulmonary vasoconstriction and impairment of oxygen delivery. We hypothesized that continuous low-dose infusion of terlipressin may reverse sepsis-related systemic arterial hypotension with reduced side effects as compared with the traditional concept of bolus administration. Twenty-seven adult sheep were instrumented for chronic study. After a baseline measurement, Salmonella typhosa endotoxin (10 ng.kg-1.min-1) was continuously administered for the next 40 h. After 16 h of endotoxemia, the surviving sheep (n = 24) were randomly assigned to be treated with either a continuous infusion of terlipressin (2 mg for 24 h), bolus injections of terlipressin (1 mg every 6 h), or placebo (normal saline; each n = 8). Continuous infusion of terlipressin permanently reversed endotoxin-induced systemic arterial hypotension (P < 0.001) and improved left ventricular stroke work index in all sheep (P < 0.05). Intermittent bolus injections of terlipressin were linked to decreases in heart rate and cardiac index and increases in pulmonary vascular resistance index (each, P < 0.001). These unwanted side effects were prevented by continuous low-dose infusion of the drug. In conclusion, continuous infusion of terlipressin stabilized hemodynamics and improved myocardial performance in endotoxemic ewes without obvious side effects. Continuous low-dose terlipressin infusion may represent a useful alternative treatment of arterial hypotension related to sepsis and systemic inflammatory response syndrome.

Background:It is unclear as to which SLE patients respond favorably to belimumab (BEL), and the impact of such treatment on peripheral blood immunophenotype in this population remains unknown.Objectives:This study aimed...

SummaryBackgroundNon-facility-based antiretroviral therapy (ART) delivery for people with stable HIV might increase sustainable ART coverage in low-income and middle-income countries. Within the HPTN 071 (PopART) trial, two interventions, home-based delivery (HBD) and adherence clubs (AC), which included groups of 15–30 participants who met at a communal venue, were compared with standard of care (SoC). In this trial we looked at the effectiveness and feasibility of these alternative models of care. Specifically, this trial aimed to assess whether these models of care had similar virological suppression to that of SoC 12 months after enrolment.MethodsThis was a three-arm, cluster-randomised, non-inferiority trial, done in two urban communities in Lusaka, Zambia included in the HPTN 071 trial. The two communities were split into zones, which were randomly assigned (1:1:1) to the three treatment strategies: 35 zones to the SoC group, 35 zones to the HBD group, and 34 zones to the AC group. ART and adherence support were delivered once every 3 months at home for the HBD group, in groups of 15–30 people in the AC group, or in the clinic for the SoC group. Adults with HIV who were receiving first-line ART for at least 6 months, virally suppressed using national HIV guidelines in the last 12 months, had no other health conditions requiring the clinicians attention, live in the study catchment area, and provided written informed consent, were eligible for inclusion. The primary endpoint was viral suppression at 12 months (with a 6 month final measurement window [ie, 9–15 months]), defined as less than 1000 HIV RNA copies per mL, with a non-inferiority margin of 5%.FindingsBetween May 5 and Dec 19, 2017, 9900 individuals were screened for inclusion, of whom 2489 (25·1%) participants were enrolled into the trial: 781 (31%) in the SoC group, 852 (34%) in the HBD group, and 856 (34%) in the AC group. A higher proportion of participants had viral load measurements in the primary outcome window in the HBD (581 [61%]of 852 participants) and AC (485 [57%] of 856 participants) groups than in the SoC (390 [50%] of 781 patients) group (p=0·0021). Of the 1096 missing observations, 152 (13·8%) were attributable to either deaths (25 [16%] participants), relocations (37 [24%] participants), or lost to follow-up (90 [59%]); 690 (63·0%) participants had viral load results outside the window period; and 254 (23·2%) did not have a viral load result. The prevalence of viral suppression was estimated to be 98·3% (95% CI 96·6 to 99·7) in the SoC group, 98·7% (97·5 to 99·6) in the HBD group, and 99·2% (98·4 to 99·8) in the AC group. This gave an estimated risk difference of 0·3% (95% CI −1·5 to 2·4) for the HBD group compared with the SoC group and 0·9% (−0·8 to 2·8) for the AC group compared with the SoC group. There was strong evidence (p<0·0001) that both community ART models were non-inferior to the SoC group (p<0·0001).InterpretationCommunity models of ART delivery were as effective as facility-based care in terms of viral suppression.FundingNational Institute of Allergy and Infectious Diseases, The International Initiative for Impact Evaluation (3ie), the Bill & Melinda Gates Foundation, National Institute on Drug Abuse, National Institute of Mental Health, and President's Emergency Plan for AIDS Relief.

A scalable, integrated intervention to engage people who inject drugs in HIV care and medication-assisted treatment (HPTN 074): a randomised, controlled phase 3 feasibility and efficacy study

Therapeutic hypothermia for birth asphyxia in low-resource settings: a pilot randomised controlled trial